Cytokine Release Syndrome As a Rare Complication of Nivolumab: A Case Report

Abstract

Immune checkpoint inhibitors such as CTLA-4 and PD-1 inhibitors mediate T-cell induced tumor cell destruction by blocking malignant cells' ability to negatively regulate T cell activity. In addition to its anti-tumor effect, checkpoint inhibition can lead to loss of maintenance of self-tolerance, leading to immune-mediated adverse events (irAEs). These events can affect any organ, with pneumonitis, hepatitis, and colitis among the most commonly reported events. A rare and life-threatening reported side effect is cytokine release syndrome (CRS). CRS is a systemic inflammatory response described in a number of cancer immunotherapies, including CAR T-cell and bispecific T-cell engagers (BiTEs). The primary pathophysiology involves activation of bystander immune and non-immune cells (such as endothelial cells) leading to a massive release of inflammatory cytokines. CRS can present as a benign, flu-like syndrome, or as an overwhelming, life-threatening systemic disease characterized by hypotension, capillary leakage, disseminated intravascular coagulopathy, and multi-organ failure. IL-6 appears to play a critical role in CRS through activation of the complement and coagulation cascade. The IL-6 inhibitor tocilizumab is the only FDA-approved treatment for CRS. There have been several reported cases of checkpoint inhibitor-induced CRS reported in the literature, including a 25-year-old patient with Hodgkin's Lymphoma (Zhao L, et al. Immunotherapy 2018) and a 29-year-old patient with sarcoma (Rotz SJ, et al. Pediatr Blood Cancer 2017). CRS developed in these cases after the first and second doses of nivolumab, respectively. We now present an additional rare case of CRS from nivolumab therapy that occurred months after initiation of treatment. We present a 71-year-old male with stage IV melanoma on cycle 17 of nivolumab with a partial response who was admitted to our institution with altered mental status, hypotension, tachycardia, fever up to 104.9°F, and hypoxia requiring BiPAP. On physical exam, he was noted to have a grade 3 maculopapular rash. Lab work on presentation was notable for serum creatinine of 1.68, platelet count of 86, d-dimer > 35, and CRP of 16.1. He was started on vancomycin and piperacillin-tazobactam for suspected sepsis. After 24 hours with no improvement, he was started on 1 mg/kg methylprednisolone due to growing concern that symptoms were immune-mediated. After another 24 hours with no improvement, tocilizumab was administered for the suspicion of CRS. The patient's clinical status began to improve within one hour of treatment with resolution of fever and hypotension, as well as improvement in hypoxia and mental status. Over the next several days, his platelet count and kidney function significantly improved as well. Decreased CRP levels suggesting a blunting of his inflammatory response, and increased IL-6 levels from IL-6 receptor blockade were seen as well. He was discharged from the hospital in good condition on day 6 post-treatment after stabilization of unrelated comorbid conditions, and followed up one week after discharge at his baseline level of function. He unfortunately developed another episode of CRS six weeks after discharge and passed away despite attempted treatment with tocilizumab. CRS remains a rare, potentially life-threatening condition that requires early diagnosis and management. Although initial investigations may point to more common conditions such as infection and sepsis, a low threshold for consideration of irAEs and CRS should exist where the clinical picture warrants. There are likely many more cases in which the diagnosis is missed and appropriate treatment not given due to lack of clinical awareness. Had our patient's symptoms not been clinically recognized as CRS by the inpatient hematology team, his condition would have likely been terminal due to the presumed diagnosis of sepsis. Physician education, particularly in the ED and ICU, early consultation, and prompt implementation of specific testing and treatment with tocilizumab can lead to significantly improved outcomes as our case shows. The unfortunate second CRS event and failure to repeatedly respond to tocilizumab with his second episode reinforces the need for continued research for additional treatment options for CRS, especially in recurrent cases. Disclosures No relevant conflicts of interest to declare.

SARS-CoV-2 infections in melanoma patients treated with PD-1 inhibitors: A survey of the German ADOREG melanoma registry

“…Third, in several cases COVID-19 was associated with a cytokine release syndrome (CRS) due to a massive secretion of pro-inflammatory cytokines, and severe, acute systemic symptoms involving the IL-6-signalling pathway 6 . Similar cytokine release syndromes have been observed under checkpoint inhibition 7 . This might explain a tendency for more severe symptoms, a high rate of hospitalizations 8 and a worse outcome as reported by Robilotti et al 9 However, it remains unclear if patients on checkpoint-inhibitor treatment are truly more susceptible for a cytokine release syndrome due to COVID-19.…”

Safety and Efficacy of Immune Checkpoint Inhibitors for Patients With Metastatic Urothelial Carcinoma and End-Stage Renal Disease: Experiences From Real-World Practice

“…CRS has been observed to be triggered by several monoclonal antibodies, systemic interleukin-2, and more recently, the CD19-CD3 chimeric antigen receptor Tcell therapy (35). A few case reports have detailed lifethreatening CRS in patients after the administration of ICIs, with occurrences ranging from cycles 1 to 17 (36)(37)(38)(39). The culprit medications were anti-PD-1 and anti-LAG-3.…”

“…The culprit medications were anti-PD-1 and anti-LAG-3. Alexander et al reported the case of a patient with stage IV melanoma who received nivolumab on cycle 17 and had a CRS episode; it was controlled by tocilizumab initially, but the patient died 6 weeks later because of another CRS episode (39). Seth et al also reported a patient with alveolar soft part sarcoma who received nivolumab and had a CRS event that was resolved by tocilizumab and corticosteroids (38).…”

Systemic therapy and COVID19: Immunotherapy and chemotherapy

“…[ 16 , 17 ] In the post-platinum setting, pembrolizumab remains the preferred agent, [18] with other agents (atezolizumab, nivolumab, avelumab, durvalumab) included in treatment guidelines but not supported by randomized, phase III trials. [19] , [20] , [21] , [22] , [23] …”

“…[ 20 , 21 ] At the same time, ICI administration itself has also been reported to cause a state of “immune hyperactivation”, whereby patients can present with cytokine release syndrome (CRS) ( Figure 1 ). [22] , [23] , [24] , [25] , [26] , [27] , [28] This massive release of cytokines can result in symptoms ranging from mild constitutional symptoms (fever, malaise, and myalgias) to severe end-organ damage. A retrospective study from China of 150 patients with confirmed COVID-19 infection showed that elevated ferritin and IL-6 were predictors of death, suggesting that COVID-19 induced immune activation may be a contributing factor in increasing mortality.…”